The application is a divisional application of the application patent application with the name of 'system and method for monitoring and evaluating neuromodulation therapy', the international application date being 2017, 1-31, international application number PCT/US2017/015887, and national application number 201780009142.6.
The present application claims the benefit of U.S. provisional patent application Ser. No. 62/289,739 filed on 1/2/2016 and U.S. provisional patent application Ser. No. 62/346,710 filed on 7/6/2016, both of which are incorporated herein by reference in their entirety.
Detailed Description
Systems and methods in accordance with embodiments of the present technology may be configured to detect physiological parameters before, during, and/or after neuromodulation therapy. This information can be used to (1) predict the likelihood that a particular patient will receive a therapeutic benefit from neuromodulation therapy ("responsiveness"), and/or (2) evaluate the efficacy of a given neuromodulation therapy. Specific details of several embodiments of the present technology are described herein with reference to fig. 1A-13. While many embodiments are described with respect to devices, systems, and methods for intravascular renal neuromodulation, other applications and other embodiments in addition to those described herein are within the scope of the present technology. For example, at least some embodiments of the present technology may be effective for endoluminal neuromodulation, extravascular neuromodulation, non-renal neuromodulation, and/or therapies other than neuromodulation. It should be noted that other embodiments besides those disclosed herein are also within the scope of the present technology. Further, embodiments of the present technology may have configurations, components, and/or procedures that are different than those illustrated or described herein. Moreover, those of ordinary skill in the art will appreciate that embodiments of the present technology may have configurations, components, and/or procedures other than those illustrated or described herein, and that various embodiments may have no number of configurations, components, and/or procedures illustrated or described herein without departing from the present technology.
As used herein, the terms "distal" and "proximal" define a position or orientation relative to a clinician or clinician's control device (e.g., handle of a neuromodulation catheter). The terms "distal" and "distally" refer to a location along the length of the device away from or in a direction away from the clinician or clinician's control device. The terms "proximal" and "proximally" refer to a location along the length of the device that is near or in a direction toward the clinician or clinician's control device. The headings provided herein are for convenience only and should not be construed as limiting the disclosed subject matter.
I. Selected embodiments of catheters and systems for notification and/or evaluation of neuromodulation therapies and related methods
1A-1C are partial schematic side views of a neuromodulation/evaluation system 100 ("system 100") configured in accordance with embodiments of the present technology and shown in a different arrangement when positioned at a target site within a blood vessel V (e.g., a renal artery) of a human patient. The system 100 includes a guidewire 101 (visible only in fig. 1A) and a neuromodulation catheter 102 configured for performing neuromodulation at a target site to ablate nerves near a vessel wall. The system 100 also includes one or more controllers 104 communicatively coupled to the guidewire 101 and/or the neuromodulation catheter 102 via a wired or wireless communication link. As discussed in more detail below, the guidewire 101 and/or neuromodulation catheter 102 are configured to sense one or more physiological parameters before, during, and/or after neuromodulation therapy in order to (1) predict a likelihood of a particular patient responding to neuromodulation therapy, and/or (2) evaluate the efficacy of a given neuromodulation therapy.
Referring to fig. 1A, guidewire 101 includes an elongate member 103 having a distal portion 103a configured to be positioned at a target site within a vessel V and a proximal portion (not visible) extending outside of the patient to a handle (not shown) or other feature that allows an operator to manipulate distal portion 103 a. The guidewire 101 and/or the elongate member 103 can be sized to be slidably positioned within the lumen of the neuromodulation catheter 102. For example, in some embodiments, the elongate member 103 can have an outer diameter of less than or equal to 0.014 inches. One or more portions of the elongated member 103 may include solid wires and/or loops of wires. For example, in some embodiments, the proximal portion 103b of the elongate member 103 comprises a solid wire and the distal portion 103a comprises a wire loop. In other embodiments, the elongated member 103 comprises only solid wires or only loops, and in other embodiments, the elongated member 103 comprises other suitable components and/or configurations. In addition, the elongate member 103 may have a uniform stiffness along its length, or may have a stiffness that varies along its length.
The guidewire 101 further includes one or more sensing elements 105 (shown schematically and individually identified as 105a-105 c) positioned along the distal portion 103a and configured to obtain one or more measurements related to one or more physiological parameters (e.g., hemodynamic parameters) of the patient. Representative sensing elements 105 include one or more of an electrocardiogram ("ECG") unit, a pressure sensor, a temperature sensor, a flow sensor (e.g., a doppler velocity sensor or an ultrasonic flow meter), an impedance sensor, a flow rate sensor, a chemical sensor, a biological sensing element, an electrochemical sensor, a hemodynamic sensor, an optical sensor, and/or other suitable sensing devices. The measured values obtained by the sensing element 105 and/or physiological parameters derived from one or more measured values obtained by the sensing element 105 include, for example, heart rate, temperature, blood pressure (e.g., systolic, diastolic, mean), blood flow rate, blood flow velocity, blood vessel diameter, vessel segment volume, blood vessel cross-sectional area, vasodilation, renal pulse wave velocity, arterial (e.g., renal artery) input impedance (frequency domain), total renal artery resistance, renal artery capacitance, reflected pressure wave amplitude, enhancement index, blood flow reserve, resistance index, capacitance reserve, hematocrit, and/or any relevant and/or derivative (e.g., raw data values, including voltage and/or other direct measurements) of the foregoing measured values and parameters. It should be appreciated that the foregoing list is provided as an example only, and that in other embodiments the sensing element 105 may be adapted to obtain additional/different parameters. In the illustrated embodiment, the guidewire 101 includes three sensing elements 105. However, in other embodiments, the guidewire 101 may include one, two, or more than three sensing elements 105. Additionally, in particular embodiments, the guidewire 101 may beDoppler guide wire (Volcano Corporation, san Diego, calif.) or ComboXT guidewire (Volcano Corporation, san Diego, CA).
As best shown in fig. 1B, the neuromodulation catheter 102 includes an elongate shaft 106 configured for slidable delivery over the guidewire 101. The elongate shaft 106 has a distal portion 106a configured to be positioned intravascularly at a target site within the vessel V and a proximal portion 106b extending outside the patient to a handle (not shown) or other feature that allows an operator to manipulate the distal portion 106a of the shaft 106. As shown in fig. 1B and 1C, the neuromodulation catheter 102 is transitionable between a first state or arrangement (fig. 1B) in which a distal portion of the neuromodulation catheter 102 is at least substantially straight, and a second state or arrangement (fig. 1C) in which the distal portion of the neuromodulation catheter 102 is transitionable or otherwise expands into a spiral/helical shape.
Referring also to fig. 1B and 1C, the neuromodulation catheter 102 includes a plurality of energy delivery elements, such as electrodes 110 (individually identified as first through fourth electrodes 110a-110d, respectively) spaced along the distal portion 106a of the shaft 106. In the illustrated embodiment, the neuromodulation catheter 102 includes four electrodes 110. However, in other embodiments, the neuromodulation catheter 102 may include one, two, three, or more than four electrodes 110, and/or may include different energy delivery elements. The electrode 110 is configured to deliver nerve modulation energy to a target site to modulate or ablate a nerve (e.g., a renal nerve) in the vicinity of the target site. As described in more detail below with reference to fig. 5, the electrode 110 and/or other features at the distal portion 106a of the shaft 106 may also be configured to apply stimulation at and/or near the target site before and/or after neuromodulation, and detect a response (e.g., a hemodynamic response) resulting from the stimulation.
In other embodiments, neuromodulation catheter 102 may include electrodes, transducers, or other elements to deliver energy using other suitable neuromodulation modalities to modulate nerves, such as pulsed electrical energy, microwave energy, optical energy, ultrasound energy (e.g., intravascular delivery ultrasound, extracorporeal ultrasound, and/or High Intensity Focused Ultrasound (HIFU)), direct thermal energy, radiation (e.g., infrared radiation, visible radiation, and/or gamma radiation), and/or other suitable types of energy. In certain embodiments, the neuromodulation catheter 102 may be configured for cryotherapy, and cryocooling may be applied to the blood vessel V with a refrigerant (e.g., via a balloon catheter that circulates the refrigerant). In still other embodiments, the neuromodulation catheter 102 is configured for chemical-based therapy (e.g., drug infusion), and the neuromodulation catheter 102 may apply one or more chemicals to the treatment site to achieve neuromodulation. Such chemicals may include neurotoxins, antagonists (e.g., citrulline), and/or tissue necrosis inducers (e.g., ethanol). In such embodiments, the pattern of neuromodulation (e.g., RF, ultrasound, chemical ablation, cryoablation) may be different from the pattern of stimulation (e.g., electrical stimulation or chemical stimulation).
The dimensions (e.g., outer diameter and length) of the coiled/helical portion of the shaft 106 may be selected to accommodate a vessel or other body lumen in which the distal portion 106a of the neuromodulation catheter 102 is designed to be delivered. For example, the axial length of the spiral/helical portion of the shaft 106 may be selected to be no longer than the patient's renal artery (e.g., typically less than 7 cm) and to have a diameter (e.g., about 2-10 mm) that accommodates the inner diameter of a typical renal artery. In other embodiments, the coiled/helical portion of the shaft 106 may have other dimensions depending on the body lumen in which the shaft is configured to be deployed. In further embodiments, the distal portion 106a of the shaft 106 may have other suitable shapes (e.g., semicircular, curved, straight, etc.), and/or the neuromodulation catheter 102 may include a plurality of support members configured to carry one or more electrodes 110. The distal portion 106a of the shaft 106 may also be designed to apply a desired outward radial force to the vessel when expanded to a spiral/helical deployment state (shown in fig. 1C) to place the one or more electrodes 110 in contact with the vessel wall.
As shown in fig. 1B and 1C, the distal portion 106a of the neuromodulation catheter 102 may optionally include an outlet 112 configured to provide acute infusion of a medicament adapted to stimulate a blood vessel V or an adjacent nerve to cause a hemodynamic or hyperemic response (e.g., vasodilation). In the illustrated embodiment, for example, the outlets 112 are positioned near the electrodes 110 such that the agent may flow distally through the vessel toward the electrodes 110 after injection, but in other embodiments, the outlets 112 may be positioned at other locations along the neuromodulation catheter 102 (e.g., between the electrodes 110 or distal to the electrodes). The outlet 112 may be in fluid communication with a lumen (not visible) that extends through the neuromodulation catheter 102 and is connected to a reservoir of a medicament (not shown). Suitable agents may include vasodilators such as adenosine, bradykinin, dipyridamole, papaverine, and/or sympathomimetic agents such as epinephrine, norepinephrine, angiotensin II, and the like. In the case of sympatholytic agonists, the lack of an immediate hemodynamic response by the patient may indicate effective ablation. In addition to or in lieu of direct pharmacological stimulation, the sympathetic nervous system ("SNS") may be stimulated by external non-pharmacological methods, such as cold pressurized stimulation (e.g., immersing the patient's hand in ice water), squeezing the rubber bulb by the patient, administering neuropsychological stress to the patient (e.g., a Stroop color test), and the like. As described above, the outlet 112 is an optional component that may not be included in some embodiments.
The neuromodulation catheter 102 may also include at least one sensing element 114 (shown schematically) and/or other device configured to detect one or more physiological parameters of the patient before, during, and/or after energy delivery. The sensing element 114 may be similar to any of the sensing elements 105 described above for use with the guidewire 101. Similarly, the measurements obtained by the sensing element 114 and/or the physiological parameter derived from the one or more measurements obtained by the sensing element 114 may be the same or similar to any of the measurements and/or physiological parameters described above with respect to the guidewire 101 and sensing element 105.
Although the embodiment of the neuromodulation catheter 102 shown in fig. 1A-1C has a spiral/helical configuration, in other embodiments, the neuromodulation catheter may have other suitable shapes, sizes, and/or configurations. Other suitable devices and techniques are described, for example, in U.S. patent application Ser. No. 12/910,631, U.S. patent application Ser. No. 13/279,205, U.S. patent application Ser. No. 13/279,330, U.S. patent application Ser. No. 13/281,360, U.S. patent application Ser. No. 13/281,361, PCT application Ser. No. 11/57754, U.S. patent application Ser. No. 61/646,218, U.S. patent application Ser. No. 13/793,647, U.S. patent application Ser. No. 61/961,874, U.S. patent application Ser. No. 13/961,874, and U.S. patent application Ser. No. 13/670,452. All of the above applications are incorporated by reference herein in their entirety. Non-limiting examples of devices and systems include SYMPLICITY FLEXTM catheters, SYMPLICITY SPYRALTM multi-electrode RF ablation catheters, and Arctic Front AdvanceTM cardiac cryoablation systems.
In some embodiments, the system 100 includes a console (not shown), and the controller 104 is integrated with the console. In such embodiments, the console may be configured to communicate with both the sensor 105 of the guidewire 101 and the neuromodulation catheter 102 via wireless and/or wired communication links. For example, in some embodiments, the console may include a separate access port for receiving a wired connection of the guidewire 101 and the neuromodulation catheter 102. In other embodiments, the console may include a single access port that may be used with both the guidewire 101 and the neuromodulation catheter 102 at the same time or with one of them at a time. In other embodiments, the system 100 may include two consoles, a first console configured to communicate with the guidewire 101 and a second console configured to communicate with the neuromodulation catheter 102.
A. selected methods of predicting responsiveness of a patient to neuromodulation therapy
Prior to delivering neuromodulation energy, it may be advantageous for the practitioner to determine one or more physiological parameters of the patient based on one or more baseline measurements. Such baseline parameters are useful not only in assessing the efficacy of neuromodulation therapy, but also in identifying whether a particular patient will therapeutically benefit from neuromodulation therapy. For example, certain physiological parameters related to hemodynamics may particularly provide information regarding the likelihood that a patient would benefit from neuromodulation therapy applied at a particular anatomical location. For example, it is believed that renal artery pulse velocity may be a predictive marker for selecting responders to renal artery neuromodulation. In particular, recent studies have found that a higher baseline renal artery pulse rate is associated with a 6 month decrease in systolic blood pressure. Accordingly, the system 100 of the present technology is configured to detect and analyze one or more physiological parameters of a patient to inform a practitioner to make a decision to proceed with neuromodulation therapy.
Fig. 2 is a block diagram illustrating a method 200 for predicting responsiveness of a patient to neuromodulation therapy in accordance with the present technique. The method 200 may be implemented using the system 100 described above with reference to fig. 1A-1C and/or other suitable systems for identifying patient responders to neuromodulation therapy. As shown in fig. 2, method 200 includes advancing a guidewire 101 (fig. 1A) to a target site within a blood vessel V (e.g., a renal artery) of a human patient, and positioning a distal portion 103a of the guidewire 101 at the target site along a portion of the blood vessel V in a substantially straight configuration (block 202) (see fig. 1A). When the guidewire 101 is positioned at the target site, the method 200 includes obtaining one or more measurements related to one or more physiological parameters of the patient via the sensing element 105 (block 204), and in some embodiments, transmitting the obtained measurements to the controller 104 and/or another feature of the system 100. The obtained measurements may then be used to determine a physiological parameter indicative of the patient's responsiveness to neuromodulation therapy, such as wave velocity at the target site (block 206). The wave velocity c may be calculated by one or more established formulas, e.g., the "sum of squares" equation:
where p=pressure, u=velocity, ρ=density of blood. The wave velocity c may also be estimated solely from the pressure waveform morphology (irrespective of velocity). It should be appreciated that other methods for determining the wave velocity are within the scope of the present disclosure.
The method 200 also includes comparing the physiological parameter to a predetermined threshold (block 208) to determine whether the patient is likely to benefit therapeutically from neuromodulation therapy (i.e., whether the patient is a "responder" or a "non-responder"). As used herein, the term "threshold" is used to refer to a standardized or patient-specific metric, which may be a single value or a range of values.
In various embodiments, comparing the determined physiological parameter to a predetermined threshold may be performed automatically by the controller 104 and/or another feature of the system 100. Based on the comparison, the controller 104 may provide an indication to the operator of whether the patient is a responder or a non-responder. For example, in embodiments in which the controller 104 calculates the renal wave velocity, if the renal wave velocity is above or outside of a predetermined threshold, the controller 104 may indicate that the patient may be a non-responder (block 212) or have a low likelihood of benefiting from neuromodulation therapy. Additionally, in some embodiments, the controller 104 may also recommend not to continue neuromodulation therapy. However, if the renal wave velocity is below or within the predetermined threshold, the controller 104 may indicate that the patient is likely to be a responder (block 210), and may suggest, in some embodiments, that neuromodulation therapy be continued. In particular embodiments, for example, controller 104 may have a display, such as a text display, an indicator light, and/or other suitable indicator, that visually indicates whether the patient is a responder.
In those procedures where the baseline measurement indicates that the patient is likely to be a responder and the operator chooses to continue the neuromodulation therapy, the operator may then advance the neuromodulation catheter 102 over the guidewire 101 to the target site, as shown in fig. 1B. The operator may then withdraw the guidewire 101 to a position proximal to the distal portion 106a of the neuromodulation catheter 102 to deploy the neuromodulation catheter 102 (as shown in fig. 1C) and begin delivering neuromodulation energy at the target site.
In some embodiments, it may be advantageous to leave a portion of the guidewire 101 distal to the distal end of the neuromodulation catheter 102 when deploying the neuromodulation catheter 102, such that the one or more sensing elements 105 remain positioned in the vessel lumen and are capable of sensing one or more physiological parameters. For example, fig. 3 illustrates one embodiment of a system 300 configured in accordance with the present technique, shown in a deployed configuration, including a guidewire 301 (only the distal portion is visible) having a flexible region along its distal portion that allows the distal portion 106a of the neuromodulation catheter 102 to assume its deployed configuration while the guidewire 301 remains positioned in the lumen of the elongate shaft 106 at the distal portion 106 a. To deploy the neuromodulation catheter 102, the operator may advance the neuromodulation catheter 102 over the guidewire 301 until the distal portion 106a of the neuromodulation catheter 102 is aligned with the flexible region and allowed to assume its preset shape. As shown in fig. 3, even when the neuromodulation catheter 102 is in its deployed configuration, the distal region 309 of the guidewire 301 remains distal of the neuromodulation catheter 102, as does the sensing element 305 positioned along the exposed distal region 309. Thus, at least the exposed sensing element 305 may continue to detect one or more physiological parameters while the neuromodulation catheter 102 is performing neuromodulation therapy.
In some cases, it may be advantageous for a practitioner to identify one or more locations in the blood vessel that are more suitable for effective ablation (i.e., increased renal nerve damage and fewer lesions). To identify such a location, the practitioner may utilize one or more physiological measurements and/or parameters associated with the hemodynamics. For example, vascular regions exhibiting abnormal hemodynamics (e.g., turbulence and secondary flow) may not be particularly suitable for neuromodulation therapy, and medical practitioners may use such information to avoid administering neuromodulation therapy in those regions. Moreover, a comparison of hemodynamic physiological measurements and/or parameters between two or more regions of a blood vessel may inform a practitioner whether and/or which particular portion of the blood vessel is to be treated. For example, a low ratio of branch to main vessel flow rate may indicate that branch treatment is less (or more) desirable in some cases.
In certain embodiments, physiological measurements or parameters may be determined at branches of a blood vessel (e.g., two branch blood vessels extending after a renal artery bifurcation) and/or at a main blood vessel (e.g., a renal artery), and the measurements or parameters may be compared to one another to select a location at which to apply neuromodulation therapy. For example, hemodynamic properties (e.g., pulse wave velocity, distensibility, etc.) may be acquired in a steady state or instantaneously in response to a stimulus (e.g., pulse wave velocity, distensibility, etc.) at two or more different regions of a blood vessel (e.g., a branch vessel and a main vessel, a first branch vessel and a second branch vessel, etc.) (described in further detail below). The two properties may be compared to each other and if the two values are heterogeneous, the practitioner may choose not to apply therapeutic neuromodulation to less responsive vessels or vessel regions. Thus, even if the main vessel, branch vessel, or vessel region alone meets the hemodynamic criteria of therapy, treating a relatively less responsive vessel or branch vessel may be less beneficial.
In some embodiments, the sensing element 114 of the neuromodulation catheter 102 may also be used to automatically detect one or more physiological parameters of the patient, and transmit the measurements to the controller 104 for processing.
It should be appreciated that while the guidewire 101/301 and neuromodulation catheter 102 described above are configured for "on-wire" delivery of the neuromodulation catheter 102, other configurations are within the scope of the present disclosure. For example, in some embodiments, the neuromodulation catheter 102 and guidewire 101/301 may be configured as a "rapid exchange" system. In other embodiments, the neuromodulation catheter 102 and guidewire 101/301 may be configured for parallel delivery. In further embodiments, the neuromodulation catheter 102 and guidewire 101/301 may be delivered sequentially. Additionally, in some embodiments, the system 100 may include a delivery sheath (not shown) configured to house the neuromodulation catheter 102 and/or the guidewire 101/301 during delivery.
B. methods of assessing efficacy of neuromodulation therapies
Successful or effective neuromodulation therapy (i.e., when the nerve is ablated to a desired extent) is expected to result in a hemodynamic response that can be reflected by local and/or global changes in hemodynamic physiological parameters (e.g., blood flow, blood pressure, and vessel diameter). As described below, the system 100 of the present technology is configured to detect and evaluate such changes in hemodynamic parameters before, during, and/or after neuromodulation therapy.
Fig. 4 is a block diagram illustrating a method 400 for assessing the efficacy of neuromodulation therapies, in accordance with embodiments of the present technique. Method 400 may be implemented using system 100 described above with reference to fig. 1A-1C, fig. 3, and/or other suitable systems for assessing the efficacy of neuromodulation therapies. For example, the guidewire 101, neuromodulation catheter 102, and/or controller 104 may be used to perform the various steps of the method 400. As shown in fig. 4, a method 400 includes positioning a guidewire 101 at a target site along a portion of a blood vessel V of a human patient (referring to fig. 1A) prior to delivering neuromodulation energy, and obtaining a baseline measurement via a sensing element 105 positioned (or otherwise coupled) along the guidewire 101 (block 402). The method 400 further includes transmitting the obtained measurements to the controller 104, and determining one or more baseline physiological parameters based on the obtained measurements (block 404). In some embodiments, the obtained baseline measurements and/or the determined baseline physiological parameters may be stored in a memory of the controller and/or in another feature of the system 100. After obtaining the baseline measurement, the method 400 optionally includes utilizing the baseline measurement to determine one or more physiological parameters and comparing the determined physiological parameters to a predetermined threshold to predict whether the patient is a responder or a non-responder, as described in detail above with reference to fig. 2.
If the operator chooses to continue the neuromodulation therapy, the method 400 includes advancing the neuromodulation catheter 102 over the guidewire 101 to the target site (see fig. 1B), and then withdrawing the guidewire 101 through the lumen of the neuromodulation catheter at least to a position within the lumen adjacent the distal portion 106a of the elongate shaft 106. With the guidewire 101 withdrawn, the distal portion 106a is transitioned to its deployed configuration such that the electrode 110 contacts the vessel wall (see fig. 1C). As shown in block 406, the neuromodulation catheter 102 may then perform neuromodulation at the target site to ablate nerves adjacent the vessel wall. For example, method 400 may include applying RF energy (e.g., via an electrode), pulsed electrical energy, microwave energy, optical energy, ultrasound energy (e.g., intravascular delivery ultrasound, in vitro ultrasound, and/or HIFU), direct thermal energy, radiation, cryocooling, chemical-based treatment, and/or other suitable types of neuromodulation energy.
After performing the neuromodulation therapy, the guidewire 101 may be advanced distally within the lumen of the elongate shaft 106, thereby converting the distal portion 106a into a generally straight, low profile configuration (see fig. 1B). The neuromodulation catheter 102 may then be withdrawn from the target site to expose the distal portion 103a of the guidewire 101 (see fig. 1A). The method 400 further includes obtaining measurements related to one or more physiological parameters after neuromodulation therapy via the exposed sensing element 105 (block 408), and transmitting the obtained measurements to the controller 104. The obtained measurements may then be used to determine one or more physiological parameters, as indicated in block 410. In some embodiments, the obtained post-neuromodulation measurements and/or the determined post-neuromodulation physiological parameters may be stored by a memory of the controller and/or another feature of the system 100.
Physiological parameters (e.g., vessel impedance, vessel diameter, etc.) after and before neuromodulation may then be compared to detect changes, if any, in the corresponding parameters as a result of neuromodulation therapy (block 412). In various embodiments, the comparison may be performed automatically by the controller 104 and/or another feature of the system 100. In some embodiments, the difference between the post-neuromodulation parameter and the pre-neuromodulation parameter may be compared to a threshold (block 414). For example, the threshold may be equal to a percentage decrease (e.g., 15% decrease, 20% decrease, 50% decrease, 100% decrease, etc.) in one or more parameters (e.g., impedance or vessel diameter, etc.), a predetermined impedance or diameter value associated with effective neuromodulation, and/or a value based on other factors associated with successful neuromodulation. If the difference is greater than or equal to the predetermined threshold, the operator may choose to stop neuromodulation therapy (block 416). If the difference is less than the threshold, the operator may choose to apply one or more additional rounds of neuromodulation energy to the treatment site using the same energy level or a higher energy level, and then detect a hemodynamic response (e.g., a change in vascular impedance or diameter), as described above. Alternatively or additionally, the operator may reposition the distal portion 106a of the shaft 106 along the vessel V to apply neuromodulation energy to a different treatment site and measure a hemodynamic response (e.g., vessel impedance or diameter) at the new treatment site.
While many hemodynamic parameters may be detected without the application of a stimulus, in some procedures it may be beneficial to additionally or alternatively stimulate nerves at or near the neuromodulation site before and after neuromodulation therapy, and detect changes in hemodynamic response resulting from each stimulus. As described in detail below with reference to fig. 5, the system 100 may be configured to apply or deliver electrical and/or pharmaceutical stimulation to a blood vessel to stimulate nerves at or near a target site. As used herein, stimulation refers to stimulation that is sufficient to cause a neural response in a nerve (e.g., renal nerve) in the vicinity of vessel V, but not so large that they permanently affect nerve function. The stimulus may be applied proximal to the neuromodulation site, distal to the neuromodulation site, and/or on either side of the neuromodulation site. For example, in certain embodiments, the stimulus is applied at a vascular orifice (e.g., renal artery orifice). However, in other embodiments, the stimulus may be applied at other suitable locations.
When the nerve is active (i.e., conducting a signal), the afferent nerve will respond to the stimulus and cause a hemodynamic response. The hemodynamic response may be measured by detecting changes in vessel dimensions (e.g., diameter, cross-sectional area, and segment volume), pressure within the vessel, blood flow through the vessel, heart rate, and/or other parameters indicative of the hemodynamic response. It is expected that after the nerve has been effectively ablated to a desired extent, the hemodynamic response to the stimulus will be eliminated or at least reduced, as the afferent nerve has been ablated or modulated. Thus, it is contemplated that the hemodynamic response to the stimulus is compared before and after neuromodulation to indicate whether neuromodulation therapy was successful.
Fig. 5 is a block diagram illustrating a method 500 for assessing the efficacy of neuromodulation therapies, in accordance with embodiments of the present technique. The method 500 may be implemented using the system 100 described above with reference to fig. 1A-1C, fig. 3, and/or other suitable systems for assessing the efficacy of neuromodulation therapies. For example, the guidewire 101, neuromodulation catheter 102, and/or controller 104 may be used to perform the various steps of the method 500. As shown in fig. 5, method 500 includes positioning a guidewire 101 at a target site along a portion of a blood vessel V of a human patient (see fig. 1A) prior to delivering neuromodulation energy, and obtaining a baseline measurement via a sensing element 105 positioned (or otherwise coupled) along the guidewire 101 (block 502). Alternatively or additionally, the method 500 may include advancing the neuromodulation catheter 102 over the guidewire 101 to the target site, and positioning the neuromodulation catheter 102 in a substantially straight configuration along a portion of the blood vessel V (fig. 1B). The sensing element 114 of the neuromodulation catheter 102 may be used to obtain baseline measurements prior to delivering neuromodulation energy.
After obtaining the baseline measurement but before applying neuromodulation energy via the electrode, and when neuromodulation catheter 102 is positioned at the target site in a substantially straight configuration (fig. 1B), electrode 110 may apply electrical stimulation at the target site and/or neuromodulation catheter 102 may release pharmacological stimulation at the treatment site via outlet 112 (block 504). In some embodiments, stimulation may additionally or alternatively be applied by one or more electrodes disposed at a distal portion of the guidewire 101, one or more electrodes associated with a separate catheter (e.g., positioned at or near a target site), external acoustic stimulation devices, and other suitable stimulation devices and methods. The electrode 110, the sensing element 114, and/or one or more sensing elements 105 associated with the guidewire 101 may then obtain measurements related to the physiological parameter after stimulation (block 506). As indicated at block 508, the method 500 further includes determining a baseline metric (Δpb) that is the difference between corresponding measurements obtained before and after stimulation.
At any time prior to applying neuromodulation energy, method 500 optionally includes utilizing the baseline measurements to determine one or more physiological parameters and comparing the determined physiological parameters to a predetermined threshold to predict whether the patient is a responder or a non-responder, as described in detail above with reference to fig. 2.
If the operator chooses to continue with neuromodulation therapy, the method 500 includes withdrawing the guidewire 101 through the lumen of the neuromodulation catheter 102 at least to a position within the lumen adjacent the distal portion 106a of the elongate shaft 106. With the guidewire 101 withdrawn, the distal portion 106a is transitioned to its deployed configuration such that the electrode 110 contacts the vessel wall (see fig. 1C). As shown in block 510, neuromodulation catheter 102 may then perform neuromodulation at the target site to ablate nerves adjacent the vessel wall. For example, method 500 may include applying RF energy (e.g., via an electrode), pulsed electrical energy, microwave energy, optical energy, ultrasound energy (e.g., intravascular delivery ultrasound, in vitro ultrasound, and/or HIFU), direct thermal energy, radiation, cryocooling, chemical-based treatment, and/or other suitable types of neuromodulation energy.
After performing the neuromodulation, the guidewire 101 may be advanced distally within the lumen of the elongate shaft 106, thereby converting the distal portion 106a into a generally straight, low profile configuration (see fig. 1B). The method 500 further includes obtaining measurements related to one or more physiological parameters after neuromodulation therapy via the sensing element 105, sensing element 114, and/or electrode 110 of the guidewire 101 (block 512). (a portion of the guidewire 101 may be exposed distal to the neuromodulation catheter 102 and/or the neuromodulation catheter 102 may be at least partially withdrawn from the target site along the guidewire 101 to expose the one or more sensing elements 105).
After obtaining the post-neuromodulation measurements, and while the neuromodulation catheter 102 is positioned at the target site in a substantially straight configuration (fig. 1B), the electrodes 110 may apply electrical stimulation at the target site and/or the neuromodulation catheter 102 may release pharmacological stimulation at the treatment site via the outlet 112 (block 514). In some embodiments, stimulation may additionally or alternatively be applied by one or more electrodes disposed at a distal portion of the guidewire 101, one or more electrodes associated with a separate catheter (e.g., positioned at or near a target site), external acoustic stimulation devices, and other suitable stimulation devices and methods. The electrode 110, sensing element 114, and/or one or more sensing elements 105 associated with the guidewire 101 may then obtain measurements related to the post-neuromodulation, post-stimulation physiological parameter (block 516). As indicated at block 518, the method 500 further includes determining a post-neuromodulation metric (Δpp) that is the difference between corresponding measurements obtained after neuromodulation, before stimulation, and after neuromodulation, after stimulation.
The difference (Δp) between the baseline metric (Δpb) and the post-neuromodulation metric (Δpp) may then be compared to detect a change in the corresponding metric (representative of the physiological parameter) as a result of the neuromodulation therapy (block 520). In various embodiments, the comparison may be performed automatically by the controller 104 and/or another feature of the system 100. In some embodiments, the difference between the post-neuromodulation parameter and the pre-neuromodulation parameter may be compared to a threshold (block 520). For example, the threshold may be equal to a percentage decrease (e.g., 15% decrease, 20% decrease, 50% decrease, 100% decrease, etc.) in one or more parameters (e.g., impedance or vessel diameter, etc.), a predetermined impedance or diameter value associated with effective neuromodulation, and/or a value based on other factors associated with successful neuromodulation. If the difference is greater than or equal to the predetermined threshold, the operator may choose to stop neuromodulation therapy (block 522). If the difference is less than the threshold, the operator may choose to apply one or more additional rounds of neuromodulation energy to the treatment site using the same energy level or a higher energy level, and then detect a hemodynamic response (e.g., a change in vascular impedance or diameter), as described above. Alternatively or additionally, the operator may reposition the distal portion 106a of the shaft 106 along the vessel V to apply neuromodulation energy to a different treatment site and measure a hemodynamic response (e.g., vessel impedance or diameter) at the new treatment site.
Other devices, systems, and methods for assessing the efficacy of neuromodulation therapies suitable for use with the system 100 and/or guidewire 101 of the present technology are described in PCT application No. PCT/US15/53499, filed on 1 month 10 2015, and U.S. patent application No. 13/670,452, filed on 6 month 11 2012, both of which are incorporated herein by reference in their entirety.
Accordingly, it is contemplated that real-time indications of nerve damage are provided by the system 100 to a clinician to determine whether successful neuromodulation therapy has occurred. Thus, the clinician does not need to wait until after the procedure to determine if the treatment is effective. While neuromodulation catheter 102 is still within vessel V, any additional energy application required to achieve neuromodulation may be performed. Thus, the system 100 can facilitate the implementation of efficient and effective neuromodulation therapies.
Fig. 6 is a partial schematic diagram of a treatment system 600 ("system 600") configured in accordance with yet another embodiment of the present technology. The system 600 may include various features similar to the systems 100 and 300 described above with respect to fig. 1A-1C and 3, and may be used to implement the various methods 200 and 400 described above. As shown in fig. 6, the system 600 includes a neuromodulation catheter 602, a console 604, and a cable 606 extending therebetween. The neuromodulation catheter 602 can include an elongate shaft 608 having a proximal portion 608b, a distal portion 608a, a handle 610 operably connected to the shaft 608 at the proximal portion 608b, and a neuromodulation assembly 620 operably connected to the shaft 608 at the distal portion 608 a. Shaft 608 and neuromodulation assembly 620 may be 2, 3, 4, 5, 6, or 7French, or another suitable size. As shown in fig. 6, the neuromodulation assembly 620 may include a support structure 622 carrying an array of two or more electrodes 624. The electrodes 624 may be configured to apply electrical stimulation (e.g., RF energy) to a target site within or near the patient, temporarily stun a nerve, deliver neuromodulation energy to the target site, and/or detect vascular impedance. In various embodiments, certain electrodes 624 may be dedicated to applying stimulation and/or detecting impedance, and neuromodulation assembly 620 may include other types of therapeutic elements that provide neuromodulation therapy using various modalities (e.g., cryotherapeutic cooling, ultrasonic energy, etc.).
The distal portion 608a of the shaft 608 is configured to move within a lumen of a human patient and position the neuromodulation assembly 620 within the lumen or otherwise proximate a target site of the lumen. For example, shaft 608 may be configured to position neuromodulation assembly 620 within a blood vessel, a tube, an airway, or another naturally occurring lumen within a human body. In certain embodiments, intravascular delivery of the neuromodulation assembly 620 includes inserting a guidewire (not shown) percutaneously into a body lumen of a patient and moving the shaft 608 and/or the neuromodulation assembly 620 along the guidewire until the neuromodulation assembly 620 reaches a target site (e.g., a renal artery). For example, the distal end of the neuromodulation assembly 620 may define a channel for engaging a guidewire for delivering the neuromodulation assembly 620 using on-wire (OTW) or rapid-exchange (RX) techniques. In other embodiments, the neuromodulation catheter 602 may be a steerable or non-steerable device configured for use without a guidewire. In still other embodiments, the neuromodulation catheter 602 may be configured for delivery via a guiding catheter or sheath (not shown).
Once at the target site, neuromodulation assembly 620 may be configured to apply stimulation, detect the resulting hemodynamic response, and provide neuromodulation therapy at the target site or facilitate neuromodulation therapy (e.g., using electrodes 624 and/or other energy delivery elements). For example, the neuromodulation assembly 620 may detect vascular impedance via the electrode 624, detect blood flow via a flow sensing element (e.g., doppler velocity sensing element), detect local blood pressure within a blood vessel via a pressure transducer or other pressure sensing element, and/or detect other hemodynamic parameters. The detected hemodynamic response may be transmitted to the console 604 and/or another device external to the patient. The console 604 may be configured to receive and store the recorded hemodynamic responses for further use by a clinician or operator. For example, the clinician may use the hemodynamic response received by the console 604 to determine whether the application of neuromodulation energy is effective to modulate the nerve to a desired degree.
The console 604 may be configured to control, monitor, supply, and/or otherwise support the operation of the neuromodulation catheter 602. The console 604 may also be configured to generate a selected form and/or size of energy for delivery to tissue at a target site via the neuromodulation assembly 620, and thus the console 604 may have different configurations depending on the treatment modality of the neuromodulation catheter 602. For example, when neuromodulation catheter 602 is configured for performing electrode-based, heating element-based, or transducer-based therapy, console 604 may include an energy generator (not shown) configured to generate RF energy (e.g., monopolar and/or bipolar RF energy), pulsed electrical energy, microwave energy, optical energy, ultrasound energy (e.g., intravascular delivery of ultrasound, in vitro ultrasound, and/or HIFU), direct thermal energy, radiation (e.g., infrared, visible, and/or gamma radiation), and/or other suitable types of energy. When the neuromodulation catheter 602 is configured for cryotherapy, the console 604 may include a refrigerant container (not shown), and may be configured to supply refrigerant to the neuromodulation catheter 602. Similarly, when neuromodulation catheter 602 is configured for chemical-based therapy (e.g., drug infusion), console 604 may include a chemical reservoir (not shown) and may be configured to supply one or more chemicals to neuromodulation catheter 602.
In selected embodiments, the system 600 may be configured to deliver a monopolar electric field via one or more electrodes 624. In such embodiments, the neutral or dispersive electrode 630 may be electrically connected to the console 604 and attached to the outside of the patient's body. In embodiments including multiple electrodes 624, the electrodes 624 may independently deliver power (i.e., can be used in a monopolar fashion) simultaneously, selectively, or sequentially, and/or may deliver power between any desired combination of electrodes 624 (i.e., can be used in a bipolar fashion). Additionally, the operator may optionally be allowed to select which electrodes 624 to use for power delivery in order to create highly tailored lesion(s) within the renal artery as desired. One or more sensing elements (not shown), such as one or more temperature sensing elements (e.g., thermocouples, thermistors, etc.), pressure sensing elements, optical sensing elements, flow sensing elements, chemical sensing elements, and/or other sensing elements, may be located near, within, or integral with the electrode 624. The sensing element(s) and electrode 624 can be connected to one or more supply lines (not shown) that transmit signals from the sensing element(s) and/or transfer energy to electrode 624.
In various embodiments, the system 600 can further include a controller 614 communicatively coupled to the neuromodulation catheter 602. The controller 614 may be configured to initiate, terminate, and/or regulate operation of one or more components of the neuromodulation catheter 602 (e.g., the electrode 624), directly and/or via the console 604. In other embodiments, the controller 614 may be omitted or have other suitable locations (e.g., within the handle 610, along the cable 606, etc.). The controller 614 may be configured to execute an automatic control algorithm and/or receive control instructions from an operator. Further, the console 604 may be configured to provide feedback to the operator via the evaluation/feedback algorithm 616 before, during, and/or after the treatment procedure.
Fig. 7 (with additional reference to fig. 6) illustrates modulating a renal nerve according to an embodiment of a system 600. Neuromodulation catheter 602 provides access to renal plexus RP via intravascular path P, such as a percutaneous access site in the femoral (not shown), brachial, radial, or axillary arteries, to a target treatment site within a corresponding renal artery RA. By manipulating the proximal portion 608b of the shaft 608 from outside the intravascular path P, the clinician may advance the shaft 608 through the sometimes tortuous intravascular path P and remotely manipulate the distal portion 608a of the shaft 608 (fig. 6). In the embodiment shown in fig. 7, the neuromodulation assembly 620 is delivered intravascularly to the treatment site using a guidewire 636 in OTW technology. As previously described, the distal end of the neuromodulation assembly 620 may define a channel for receiving the guidewire 636 for delivering the neuromodulation catheter 602 using OTW or RX techniques. At the treatment site, the guidewire 636 may be at least partially withdrawn or removed, and the neuromodulation assembly 620 may be converted or otherwise moved to a deployment arrangement to record neural activity and/or deliver energy at the treatment site. In other embodiments, the neuromodulation assembly 620 may be delivered to a treatment site within an introducer sheath (not shown) with or without the use of a guidewire 636. When the neuromodulation assembly 620 is at the target site, the introducer sheath may be at least partially withdrawn or retracted and the neuromodulation assembly 620 may be converted to a deployment arrangement. In still other embodiments, the shaft 608 itself may be steerable such that the neuromodulation assembly 620 may be delivered to the treatment site without the aid of the guidewire 636 and/or the introducer sheath.
Image guidance, such as Computed Tomography (CT), fluoroscopy, intravascular ultrasound (IVUS), optical Coherence Tomography (OCT), intracardiac echocardiography (ICE), or another suitable guidance modality, or a combination thereof, may be used to assist the clinician in locating and manipulating the neuromodulation assembly 620. For example, a fluoroscopic system (e.g., including a flat panel detector, x-ray, or c-arm) may be rotated to accurately visualize and identify a target treatment site. In other embodiments, the treatment site may be determined prior to delivery of the neuromodulation assembly 620 using IVUS, OCT, and/or other suitable image mapping modalities that are capable of associating the target treatment site with identifiable anatomical structures (e.g., spinal features) and/or a radiopaque ruler (e.g., positioned below or above the patient). Further, in some embodiments, an image-guiding component (e.g., IVUS, OCT) may be integrated with the neuromodulation catheter 602 and/or extend parallel to the neuromodulation catheter 602 to provide image guidance during positioning of the neuromodulation assembly 620. For example, an image-guiding component (e.g., IVUS or OCT) may be coupled to the neuromodulation assembly 620 to provide a three-dimensional image of vasculature adjacent to the target site to facilitate positioning or deployment of the multi-electrode assembly within the target renal vessel.
Energy from the electrode 624 (fig. 6) and/or other energy delivery element may then be applied to the target tissue to induce one or more desired neuromodulation effects on a localized region of the renal artery RA and on an adjacent region of the renal plexus RP that is located immediately within, near, or immediately adjacent to the adventitia of the renal artery RA. The targeted application of energy may effect neuromodulation along all or at least a portion of the renal plexus RP. Neuromodulation generally depends at least in part on power, time, contact between the energy delivery element and the vessel wall, and blood flow through the vessel. Neuromodulation may include denervation, thermal ablation, and/or non-ablative thermal modification or injury (e.g., by sustained heating and/or resistive heating). The desired thermal heating effect may include raising the temperature of the target nerve fiber above a desired threshold to effect a non-ablative thermal change, or above a higher temperature to effect a non-ablative thermal change. For example, the target temperature may be above body temperature (e.g., about 37 ℃) but below about 45 ℃ for non-ablative thermal changes, or about 45 ℃ or higher for ablative thermal changes. The desired non-thermal neuromodulation effect may include altering an electrical signal transmitted in the nerve.
Low temperature effects may also provide neuromodulation. For example, the cryotherapeutic applicator may be used to cool tissue at a target site to provide therapeutically effective direct cell damage (e.g., necrosis), vascular damage (e.g., nutrient-free cells by damaging supply vessels), and sub-lethal sub-hypothermia with subsequent apoptosis. Exposure to cryotherapeutic cooling can lead to acute cell death (e.g., immediate death following exposure) and/or delayed cell death (e.g., during tissue thawing and subsequent over-perfusion). Embodiments of the present technology may include cooling structures at or near the inner surface of the renal artery wall such that adjacent (e.g., adjacent) tissue is effectively cooled to the depth where the sympathetic renal nerve is located. For example, the cooling structure is cooled to a degree that causes therapeutically effective low temperature renal neuromodulation. Sufficient cooling of at least a portion of the sympathetic renal nerves is expected to slow down or potentially block the conduction of nerve signals to produce an extended or permanent decrease in renal sympathetic nerve activity.
The electrodes 624 and/or other features of the neuromodulation assembly 620 may intravascularly apply stimulation to the renal artery RA and detect hemodynamic responses to the stimulation before and/or after applying neuromodulation energy to the renal artery RA. This information can then be used to determine the efficacy of neuromodulation therapy. For example, the controller 614 (fig. 6) may process the detected hemodynamic response before and after neuromodulation, and compare the change in hemodynamic response to a predetermined threshold to assess whether neuromodulation therapy is effective at the treatment site or at the particular ablation site.
Renal neuromodulation
Renal neuromodulation is the partial or complete disability or other effective destruction of the nerves of the kidney (e.g., nerves that terminate in the kidney or in structures closely related to the kidney). In particular, renal neuromodulation may include inhibiting, reducing, and/or blocking neural communication of neural fibers (e.g., efferent and/or afferent neural fibers) of the kidney. Such disablement may be long-term (e.g., a period of time of a permanent or months, years or decades) or short-term (e.g., a period of time of a minute, hour, day or week). Renal neuromodulation is expected to facilitate a systemic reduction in sympathetic tone or drive and/or to facilitate at least some specific organs and/or other bodily structures innervated by the sympathetic nerve. Thus, renal neuromodulation is expected to be effective for treating clinical conditions associated with systemic sympathetic overactivity or hyperactivity, particularly conditions associated with central sympathetic overstimulation. For example, renal neuromodulation is expected to be effective in treating conditions such as hypertension, heart failure, acute myocardial infarction, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic and end-stage renal disease, inappropriate fluid retention in heart failure, heart-kidney syndrome, polycystic kidney disease, polycystic ovary syndrome, osteoporosis, erectile dysfunction, and sudden death.
Renal neuromodulation may be induced at one or more suitable target sites during a therapeutic procedure with electrical induction, thermal induction, chemical induction, or in other suitable manners or combinations of manners. The target site may be located within or otherwise adjacent to a renal lumen (e.g., a renal artery, ureter, renal pelvis, major renal calyx, small renal calyx, or another suitable structure), and the tissue treated may include tissue at least adjacent to a wall of the renal lumen. For example, with respect to the renal artery, a therapeutic procedure may include modulating nerves in the renal plexus that are located closely within or near the adventitia of the renal artery.
Renal neuromodulation may include a cryotherapeutic modality alone or in combination with another therapeutic modality. Cryotherapy may include cooling tissue at a target site in a manner that modulates nerve function. For example, sufficient cooling of at least a portion of the sympathetic renal nerve may slow down or potentially block the conduction of nerve signals to produce an extended or permanent decrease in renal sympathetic nerve activity. This effect may occur due to cryotherapeutic tissue damage, which may include, for example, direct cell damage (e.g., necrosis), vascular or luminal damage (e.g., nutrient-free cells by disrupting supply vessels), and/or sublethal subhypothermia with subsequent apoptosis. Exposure to cryotherapeutic cooling can lead to acute cell death (e.g., immediate death following exposure) and/or delayed cell death (e.g., during tissue thawing and subsequent over-perfusion). Neuromodulation using cryotherapy in accordance with embodiments of the present technology may include cooling structures adjacent to the inner surface of the body lumen wall such that tissue is effectively cooled to the depth where sympathetic renal nerves are located. For example, in some embodiments, the cooling component of the cryotherapeutic device may be cooled to a degree that it causes therapeutically effective low temperature renal neuromodulation. In other embodiments, the cryotherapeutic modality may include cooling that is not configured to cause neuromodulation. For example, cooling may be at or above cryogenic temperatures, and may be used to control neuromodulation via another therapeutic modality (e.g., to protect tissue from neuromodulation energy).
Renal neuromodulation may include electrode-based or transducer-based treatment modalities alone or in combination with another treatment modality. Electrode-based or transducer-based therapy may include delivering electricity and/or other forms of energy to tissue at a treatment site to stimulate and/or heat the tissue in a manner that modulates nerve function. For example, sufficiently stimulating and/or heating at least a portion of the sympathetic renal nerve may slow down or potentially block the conduction of nerve signals to produce an increase or permanent decrease in renal sympathetic nerve activity. Various suitable types of energy may be used to stimulate and/or heat tissue at the treatment site. For example, neuromodulation in accordance with embodiments of the present technology may include delivering RF energy, pulsed electrical energy, microwave energy, optical energy, focused ultrasound energy (e.g., high intensity focused ultrasound energy), or another suitable type of energy, alone or in combination. The electrodes or transducers used to transfer this energy may be used alone or with other electrodes or transducers in a multi-electrode or multi-transducer array. Furthermore, energy may be applied from within the body (e.g., within the vasculature or other body lumen in a catheter-based approach) and/or from outside the body (e.g., via an applicator located outside the body). In addition, energy may be used to reduce damage to non-target tissue when target tissue adjacent to the non-target tissue is subjected to neuromodulation cooling.
Neuromodulation using focused ultrasound energy (e.g., high intensity focused ultrasound energy) may be beneficial relative to neuromodulation using other treatment modalities. Focused ultrasound is one example of a transducer-based treatment modality that may be delivered from outside the body. Focused ultrasound therapy may be performed in close association with imaging (e.g., magnetic resonance, computed tomography, fluoroscopy, ultrasound (e.g., intravascular or intraluminal), optical coherence tomography, or other suitable imaging modality. For example, imaging may be used to identify an anatomical location (e.g., a set of coordinates relative to a reference point) of a treatment location. The coordinates may then be input into a focused ultrasound device configured to change power, angle, phase, or other suitable parameter to generate an ultrasound focus region at a location corresponding to the coordinates. The focal zone may be small enough to localize the therapeutically effective heating at the treatment site while partially or completely avoiding potentially harmful damage to nearby structures. To create a focal region, the ultrasound device may be configured to pass ultrasound energy through the lens, and/or the ultrasound energy may be generated by a curved transducer or by a plurality of transducers of a phased array (curved or straight).
The heating effect of the electrode-based or transducer-based therapy may include ablation and/or non-ablation changes or damage (e.g., by continuous heating and/or resistive heating). For example, the treatment procedure may include raising the temperature of the target nerve fibers to a target temperature above a first threshold to effect a non-ablative change, or above a second, higher threshold to effect ablation. For non-ablative changes, the target temperature may be above about body temperature (e.g., about 37 ℃) but below about 45 ℃, and for ablative, the target temperature may be above about 45 ℃. For example, heating tissue to a temperature between about body temperature and about 45 ℃ may result in non-ablative changes by moderately heating the target nerve fibers or perfusing the vascular or luminal structures of the target nerve fibers. In the event that vascular structure is affected, perfusion of the target nerve fibers may be denied, resulting in necrosis of the nerve tissue. For example, heating tissue to a target temperature above about 45 ℃ (e.g., above about 60 ℃) may result in ablation by heating the target nerve fibers in bulk or perfusing the vessel or lumen structure of the target fibers. In some patients, it may be desirable to heat the tissue to a temperature sufficient to ablate the target nerve fibers or blood vessels or luminal structures, but less than about 90 ℃ (e.g., less than about 85 ℃, less than about 80 ℃, or less than about 75 ℃).
Renal neuromodulation may include a chemotherapy-based treatment modality alone or in combination with another treatment modality. Neuromodulation using chemical-based therapy may include delivering one or more chemicals (e.g., drugs or other agents) to tissue at a treatment site in a manner that modulates neural function. For example, the chemicals may be selected to generally affect the treatment site or to selectively affect some structures but not others on the treatment site. For example, the chemical may be guanethidine, ethanol, phenol, a neurotoxin, or another suitable agent selected to alter, destroy or destroy nerves. Various suitable techniques may be used to deliver chemicals to tissue at a treatment site. For example, the chemicals may be delivered via one or more needles from outside the body or within the vasculature or other body cavity. In an intravascular example, the catheter may be used to position a treatment element including multiple needles (e.g., microneedles) within a vessel, which may be retracted or otherwise blocked prior to deployment. In other embodiments, the chemicals may be introduced into the tissue at the treatment site via simple diffusion through the body lumen wall, electrophoresis, or other suitable mechanism. Similar techniques may be used to introduce chemicals that are not configured to cause neuromodulation, but rather promote neuromodulation by another therapeutic modality.
Related anatomies and physiology
As previously described, the Sympathetic Nervous System (SNS) is a branch of the autonomic nervous system as well as the enteric nervous system and parasympathetic nervous system. It is always active at basal levels (called sympathetic tone) and becomes more active during stress. As with the other parts of the nervous system, the sympathetic nervous system operates through a series of interconnected neurons. Sympathetic neurons are generally considered part of the Peripheral Nervous System (PNS), but many are located within the Central Nervous System (CNS). The sympathetic neurons of the spinal cord (which are part of the CNS) communicate with peripheral sympathetic neurons via a series of sympathetic ganglia. Within the ganglion, spinal cord sympathetic neurons are coupled to peripheral sympathetic neurons by synapses. Spinal cord sympathetic neurons are therefore referred to as presynaptic (or pre-ganglionic) neurons, while peripheral sympathetic neurons are referred to as postsynaptic (or postganglionic) neurons.
At synapses within the sympathetic ganglion, the preganglionic sympathetic neurons release acetylcholine, a chemical messenger that binds to and activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus, postganglionic neurons release mainly norepinephrine (norepinephrine). Prolonged activation may cause release of epinephrine from the adrenal medulla.
Once released, norepinephrine and epinephrine bind to adrenergic receptors on peripheral tissues. Binding to adrenergic receptors causes neuronal and hormonal responses. Physiological manifestations include dilated pupils, increased heart rate, occasional vomiting, and elevated blood pressure. Increased sweating is also observed due to binding of cholinergic receptors of sweat glands.
The sympathetic nervous system is responsible for up and down regulation or many homeostatic mechanisms in the organism. Fibers from the SNS innervate tissues in nearly every organ system, providing at least some regulatory function for physiological features such as pupil diameter, intestinal movement, and urine output. This response is also known as the sympathetic-adrenal response of the body, because preganglionic sympathetic fibers (and all other sympathetic fibers) ending in the adrenal medulla secrete acetylcholine which activates the secretion of epinephrine (adrenal hormone) and to a lesser extent norepinephrine (norepinephrine). Thus, this response, which acts primarily on the cardiovascular system, is mediated directly by impulses transmitted by the sympathetic nervous system, and indirectly by catecholamines secreted by the adrenal medulla.
Scientifically, SNS is generally regarded as an autoregulation system, i.e., a system that works without intervention through conscious thinking. Some evolutionary theorists believe that the sympathetic nervous system functions in early organisms to sustain survival because the sympathetic nervous system is responsible for initiating physical activity. One example of such an initiation is the moment before waking up, where sympathetic outflow increases spontaneously in preparation for action.
A. Sympathetic nerve chain
As shown in FIG. 8, the SNS provides a neural network that allows the brain to communicate with the body. The sympathetic nerves originate inside the spine, toward the middle of the spinal cord in the medial lateral cell column (or lateral corner), originate from the first thoracic segment of the spinal cord and are thought to extend to the second or third lumbar segment. Since its cells originate in the thoracic and lumbar regions of the spinal cord, SNS is said to have thoracic and lumbar segment outflow. The axons of these nerves pass the spinal cord through the anterior root/root. They pass near the spinal (sensory) ganglion where they enter the anterior branch of the spinal nerve. However, unlike somatic innervation, they are rapidly separated by a white branch connector that connects to the paravertebral (which is located near the spine) or anterior (which is located near the aortic bifurcation) ganglion extending alongside the spine.
To reach the target organ and gland, the axons should travel long distances in the body, and to achieve this many axons pass their information to the second cell by synaptic transmission. The ends of the axons are connected (i.e., synapses) across the space to dendrites of the second cell. The first cell (presynaptic cell) sends neurotransmitters across the synaptic cleft, where it activates the second cell (postsynaptic cell). The message is then transmitted to the final destination.
In the SNS and other components of the peripheral nervous system, these synapses occur at sites called ganglia, as described above. Cells that send their fibers are called pre-ganglion cells, while cells that leave the ganglion are called post-ganglion cells. As previously described, the ganglion cells of SNS are located between the first thoracic segment (T1) and the third lumbar segment (L3) of the spinal cord. Postganglionic cells have their cell bodies in the ganglion and burst their axes to the target organ or gland.
Ganglia include not only the sympathetic trunk, but also the cervical ganglia (superior, medial and inferior), which send the sympathetic fibers to the head and thoracic organs, as well as the celiac and mesenteric ganglia (send the sympathetic fibers to the gut).
1. Renal innervation
As shown in fig. 9, the kidneys are dominated by the Renal Plexus (RP), which is closely related to the renal arteries. The Renal Plexus (RP) is an autonomic plexus that surrounds and is embedded in the adventitia of the renal artery. The Renal Plexus (RP) extends along the renal arteries until it reaches the renal mass. Fibers leading to the Renal Plexus (RP) originate in the celiac ganglion, superior mesenteric ganglion, aortic ganglion, and aortic plexus. The Renal Plexus (RP), also known as the renal nerve, is composed primarily of sympathetic nerve components. The kidneys have no (or at least very little) parasympathetic innervation.
The ganglion pre-neuronal cell bodies are located in the medial lateral cell column of the spinal cord. The pre-ganglion axons pass through the paravertebral ganglia (which do not synapse) to become small splanchnic nerves, minimal splanchnic nerves, first lumbar splanchnic nerves, second lumbar splanchnic nerves, and travel to the celiac ganglia, superior mesenteric ganglia, and aortorenal ganglia. Postganglionic neuronal cell bodies leave celiac ganglion, superior mesenteric ganglion and aorticorenal ganglion into Renal Plexus (RP) and are distributed to renal vasculature.
2. Renal sympathetic nervous activity
Messages are transmitted in bi-directional streams through the SNS. The outgoing message may trigger a change in different parts of the body simultaneously. For example, the sympathetic nervous system may accelerate heart rate, dilate bronchial passages, reduce movement of the large intestine (movement), constrict blood vessels, increase esophageal peristalsis, cause dilation of the pupil, hair erectile (chicken skin pimples) and sweating (sweating), and blood pressure elevation. The afferent information conveys signals from various organs and sensory receptors of the body to other organs, particularly the brain.
Hypertension, heart failure, and chronic kidney disease are some of the many disease states caused by chronic activation of SNS (in particular the renal sympathetic nervous system). Chronic activation of SNS is an adaptive adverse reaction that drives the progression of these disease states. Drug management of the renin-angiotensin-aldosterone system (RAAS) has been a long-term but somewhat inefficient method of reducing SNS overactivity.
As mentioned above, the renal sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, volume overload states (e.g., heart failure), and progressive renal disease, both experimentally and in humans. Studies measuring norepinephrine spillover from kidneys to plasma using a radiotracer dilution method have shown an increase in renal Norepinephrine (NE) spill rate in primary hypertensive patients, especially young hypertensive patients, consistent with increased NE spill from the heart, consistent with the hemodynamic distribution commonly seen in early hypertension and characterized by increased heart rate, cardiac output, and renal vascular resistance. It is now known that primary hypertension is often neurogenic, often accompanied by significant sympathetic nervous system overactivity.
Activation of the cardiorenal sympathetic nerve activity is even more pronounced in heart failure, as evidenced by exaggerated increases in NE extravasation from the heart and kidneys to plasma in this patient group. From this perspective, the strong negative predictive value of renal sympathetic activation for total cause mortality and heart transplantation in congestive heart failure patients has recently been demonstrated, independent of overall sympathetic activity, glomerular filtration rate, and left ventricular ejection fraction. These findings support the insight that treatment regimens aimed at reducing renal sympathetic nerve stimulation are likely to increase survival in heart failure patients.
Chronic and end stage renal disease is characterized by increased sympathetic activation. For patients with end stage renal disease, plasma norepinephrine levels above the median have been shown to be predictive of total and cardiovascular death. The same is true for patients with diabetes or contrast nephropathy. There has been convincing evidence that sensory afferent signals from the diseased kidneys are the primary cause of initiation and maintenance of elevated central sympathetic outflow in this patient group, which promotes the occurrence of well-known adverse consequences of chronic sympathetic nerve activity, such as hypertension, left ventricular hypertrophy, ventricular arrhythmias, sudden cardiac death, insulin resistance, diabetes mellitus and metabolic syndrome.
(I) Renal sympathetic efferent activity
The renal sympathetic nerves terminate in the blood vessels, glomerular paracentesis and tubules. Stimulation of the renal sympathetic nerve results in increased renin release, increased sodium (na+) reabsorption and decreased renal blood flow. These components of renal function neuromodulation are subjected to considerable stimulation in disease states characterized by elevated sympathetic tone and significantly contribute to elevated blood pressure in hypertensive patients. Renal blood flow reduction and glomerular filtration rate due to renal sympathetic efferent stimulation may be the cornerstone of renal loss in heart-kidney syndrome, which is renal insufficiency that is a progressive complication of chronic heart failure with a clinical course that generally fluctuates with the clinical condition and treatment of the patient. Pharmacological strategies to prevent the consequences of renal efferent sympathetic nerve stimulation include centrally acting sympatholytic drugs, beta blockers (intended to reduce renin release), angiotensin converting enzyme inhibitors and receptor blockers (intended to block the effects of angiotensin II and aldosterone activation following renin release), and diuretics (intended to counteract renal sympathetic mediated sodium and water retention). However, current pharmacological strategies have significant limitations, including limited efficacy, compliance issues, side effects, and the like.
(Ii) Renal sensory afferent neural activity
The kidneys communicate with the overall structure in the central nervous system via the renal sensory afferent nerves. Several forms of "kidney injury" can induce activation of sensory afferent signals. For example, renal ischemia, a decrease in stroke volume or renal blood flow, or an adenylase abundance may trigger activation of afferent neural communications. As shown in fig. 10 and 11, the incoming communication may be from kidney to brain, or may be from one kidney to another (via the central nervous system). These afferent signals are integrated centrally and may lead to increased sympathetic outflow. This sympathetic drive is directed to the kidneys, thereby activating RAAS and inducing increased renin secretion, sodium retention, volume retention and vasoconstriction. Central sympathetic nerve activity also affects other organs and body structures (e.g., heart and peripheral vasculature) innervated by the nerves, resulting in the adverse effects of such sympathetic nerve activation, several of which also contribute to elevated blood pressure.
Physiology therefore suggests that (i) use of efferent sympathetic modulatory tissue will reduce inappropriate renin release, salt retention and reduced renal blood flow, and (ii) use of afferent sensory modulation tissue will reduce the systemic contribution of hypertension and other disease states associated with increased central sympathetic tone through its direct effects on the posterior hypothalamus and the contralateral kidneys. In addition to central hypotension of afferent renal denervation, it is expected that conditions of central sympathetic outflow to various other sympathogenic organs (e.g., heart and vasculature) would be desirably reduced.
B. Other clinical benefits of renal denervation
As mentioned above, renal denervation may be valuable in the treatment of several clinical conditions characterized by increased overall and in particular renal sympathetic nervous activity, such as hypertension, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic end-stage renal disease, inappropriate fluid retention in heart failure, cardiorenal syndrome and sudden death. Since a decrease in afferent nerve signal contributes to a systemic decrease in sympathetic tone/drive, renal denervation may also be used to treat other conditions associated with systemic sympathetic overactivity. Thus, renal denervation may also benefit other organs and body structures innervated by sympathetic nerves, including those shown in fig. 8. For example, as previously described, a reduction in central sympathetic drive may reduce insulin resistance in patients with afflicting metabolic syndrome and type II diabetes. In addition, patients with osteoporosis are also sympathetically activated and may also benefit from down-regulation of sympathetic drive with renal denervation.
C. achieving intravascular access to renal arteries
In accordance with the present technique, neuromodulation of the left and/or right Renal Plexus (RP) in close association with the left and/or right renal arteries may be achieved through intravascular pathways. As shown in fig. 12, blood moving through systole is delivered from the left ventricle of the heart through the aorta. The aorta descends through the chest and branches into the left and right renal arteries. Below the renal arteries, the aorta diverges at the left and right iliac arteries. The left and right iliac arteries descend through the left and right legs, respectively, and connect the left and right femoral arteries.
As shown in fig. 13, blood collects in the veins and returns to the heart, through the femoral vein, into the iliac vein and into the inferior vena cava. The inferior vena cava branches into the left and right renal veins. Above the renal veins, the inferior vena cava rises to deliver blood to the right atrium of the heart. From the right atrium, blood is pumped through the right ventricle into the lungs where it is oxidized. From the lungs, oxygenated blood is delivered to the left atrium. From the left atrium, oxygenated blood is delivered from the left ventricle back to the aorta.
As will be described in more detail later, the femoral artery may be accessed and cannulated at the base of a femoral triangle just below the midpoint of the inguinal ligament. The catheter may be inserted percutaneously through the access site into the femoral artery, through the iliac artery and aorta, and placed in the left or right renal artery. This includes intravascular pathways that provide minimally invasive access to the corresponding renal artery and/or other renal blood vessels.
The wrist, upper arm and shoulder regions provide other locations for introducing catheters into the arterial system. For example, in selected cases, catheterization of the radial, brachial, or axillary arteries may be used. Using standard angiographic techniques, the catheter introduced through these access points can pass through the left subclavian artery (or through the right subclavian and brachiocephalic arteries), through the aortic arch, down the descending aorta and into the renal arteries.
D. Properties and Properties of the renal vasculature
Since neuromodulation of the left and/or right Renal Plexus (RP) may be achieved through intravascular pathways in accordance with the present techniques, the nature and characteristics of the renal vasculature may impose constraints and/or be informed of the design of devices, systems, and methods for achieving such renal neuromodulation. Some of these properties and characteristics may vary over time, as well as in response to disease states (e.g., hypertension, chronic kidney disease, vascular disease, end stage renal disease, insulin resistance, diabetes, metabolic syndrome, etc.), among patient populations and/or particular patients. As explained herein, these properties and characteristics may be related to the efficacy of the procedure and the particular design of the intravascular device. The properties of interest may include, for example, material/mechanical, spatial, hydrodynamic/hemodynamic, and/or thermodynamic properties.
As previously described, the catheter may be percutaneously accessed into the left or right renal artery via a minimally invasive intravascular path. However, minimally invasive renal arterial access can be challenging, for example, because renal arteries are often extremely tortuous, may have a relatively small diameter, and/or may have a relatively short length compared to some other arteries that are routinely accessed using catheters. Furthermore, renal atherosclerosis is common in many patients, particularly those suffering from cardiovascular disease. Renal artery anatomy may also vary significantly from patient to patient, further complicating minimally invasive access. Significant inter-patient variation can be seen, for example, in relative tortuosity, diameter, length, and/or atherosclerotic plaque burden, as well as the angle of deviation of the renal artery from the aortic branch. Devices, systems and methods for achieving renal neuromodulation via intravascular access when minimally invasive access to the renal arteries should take into account these and other aspects of renal artery anatomy and their variation in patient populations.
In addition to complicating the renal artery access, details of the renal anatomy complicate the establishment of stable contact between the neuromodulation device and the luminal surface or wall of the renal artery. For example, the catheter may be hindered by a narrow space within the renal artery and by arterial bending. Furthermore, establishing consistent contact is complicated by patient movement, respiration, and/or cardiac cycle, as these factors may cause significant movement of the renal artery relative to the aorta, and the cardiac cycle may transiently dilate the renal artery (i.e., cause wall pulsation of the artery).
Even after entering the renal artery and promoting stable contact between the neuromodulation device and the luminal surface of the artery, nerves in and around the adventitia should be safely modulated by the neuromodulation device. In view of the potential clinical complications associated with such treatments, it is important that the thermal treatment be effectively applied from within the renal arteries. For example, the intima and media of the renal arteries are very susceptible to thermal injury. As discussed in more detail below, the intima-media thickness separating the vessel lumen from its adventitia means that the target renal nerve may be several millimeters from the luminal surface of the artery. Sufficient energy should be delivered to or thermally removed from the target renal nerve to modulate the target renal nerve without excessively cooling or heating the vessel wall to such an extent that the wall is frozen, dried, or otherwise potentially affected by an undesirable degree. A potential clinical complication associated with excessive heating is thrombosis caused by blood clotting flowing through an artery. In view of the potential for such thrombosis to cause renal infarction, thereby causing irreversible damage to the kidney, thermal treatment within the renal artery should be carefully applied. Thus, the complex hydrodynamic and thermodynamic conditions present in the renal arteries during treatment, particularly those that may affect the kinetics of heat transfer at the treatment site, may be important when applying energy (e.g., heating thermal energy) and/or removing heat from tissue within the renal arteries (e.g., cooling thermal conditions).
The neuromodulation device should also be configured to allow for adjustable positioning and repositioning of the energy delivery element within the renal artery, as the location of the treatment may also affect clinical efficacy. For example, it may be attractive to apply full circumferential treatment from within the renal artery, given that the renal nerves may be circumferentially spaced around the renal artery. In some cases, full-round lesions that may be caused by continuous circumferential treatment may be associated with renal artery stenosis. Therefore, it may be desirable to form more complex lesions along the longitudinal dimension of the renal artery and/or to reposition the neuromodulation device to multiple treatment locations. However, it should be noted that the benefits of producing circumferential ablation may outweigh the likelihood of renal artery stenosis, or the risk may be lessened by certain embodiments or in certain patients and that producing circumferential ablation may be the goal. In addition, variable positioning and repositioning of neuromodulation devices may prove useful in situations where the renal artery is particularly tortuous or where there is a proximal branch vessel exiting the main vessel of the renal artery, making treatment at certain locations challenging. Manipulating the device in the renal artery should also take into account mechanical damage that the device imparts to the renal artery. Movement of the device in the artery, e.g., by insertion, manipulation, cooperation with bending, etc., may cause dissection, perforation, peeling of the intima, or disruption of the internal elastic membrane.
Blood flow through the renal arteries may be temporarily occluded for a short period of time with minimal or no complications. However, prolonged occlusion should be avoided because kidney damage such as ischemia is to be prevented. It may be beneficial to avoid the occlusion altogether, or if the occlusion is beneficial for the embodiment, to limit the duration of the occlusion to, for example, 2-5 minutes.
Based on the above challenges of (1) renal artery intervention, (2) consistent and stable placement of the treatment element against the vessel wall, (3) effective application of treatment to the vessel wall, (4) positioning and possibly repositioning of the treatment device to allow multiple treatment locations, and (5) avoidance or limitation of the duration of the blood flow occlusion, various independent and dependent properties of the renal vasculature of possible interest include, for example, (a) vessel diameter, vessel length, intima-media thickness, coefficient of friction and tortuosity, (b) distensibility, stiffness and elastic modulus of the vessel wall, (c) peak systolic phase, end-diastolic blood flow velocity, and average systolic-diastolic peak blood flow velocity, and average/maximum volumetric blood flow rate, (d) specific heat capacity of the blood and/or vessel wall, thermal convection and/or radiant heat transfer of blood flow through the vessel wall treatment location, (e) renal artery movement relative to the aorta caused by respiration, patient movement and/or blood flow pulsatility, and (f) renal artery movement relative to the aorta. These properties will be discussed in more detail with respect to the renal arteries. However, depending on the device, system, and method used to achieve renal neuromodulation, such properties of the renal artery may also guide and/or constrain the design characteristics.
As mentioned above, the device located in the renal artery should conform to the geometry of the artery. The renal artery vessel diameter DRA is typically in the range of about 2-10mm, with most patient populations having DRAs of about 4mm to about 8mm and averages of about 6 mm. The renal artery vessel length LRA between the ostium of the aortic/renal artery junction and its distal branch is generally in the range of about 5-70mm, and a majority of the patient population is in the range of about 20-50 mm. Since the target renal plexus is embedded within the adventitia of the renal artery, the composite intima-media thickness IMT (i.e., the radially outward distance from the luminal surface of the artery to the adventitia containing the target neural structure) is also significant and generally ranges from about 0.5-2.5mm, on average about 1.5mm. Although a certain depth of treatment is important for reaching the target nerve fibers, the treatment should not be too deep (e.g., >5mm from the inner wall of the renal artery) to avoid non-target tissues and anatomical structures such as the renal veins.
An additional property of the renal artery that may be of interest is the extent of renal movement relative to the aorta caused by respiratory and/or blood flow pulsations. The patient's kidney at the distal end of the renal artery may move 4 "toward the head with a respiratory offset. This may impart significant motion to the renal arteries connecting the aorta and kidneys, thereby requiring a unique balance of rigidity and flexibility from the neuromodulation device to maintain contact between the energy delivery element and the vessel wall during the respiratory cycle. Furthermore, the angle of deviation between the renal artery and the aorta may vary significantly from patient to patient and may also vary dynamically within the patient, for example due to renal movement. The angle of departure may generally be in the range of about 30 ° -135 °.
Additional examples
1. A neuromodulation/evaluation system, comprising:
A neuromodulation catheter comprising an elongate shaft defining a lumen therethrough, a proximal portion, and a distal portion, wherein the distal portion is configured to deliver therapeutic neuromodulation at a target site in a renal blood vessel of a human patient;
A guidewire configured to be slidably positioned within a lumen of the elongate shaft, the guidewire having a distal portion and a sensing element positioned along the distal portion, wherein the sensing element is configured to detect physiological measurements at a target site, and
A controller configured to be communicatively coupled to the sensing element, wherein the controller is further configured to:
obtaining a physiological measurement via the sensing element;
Determining a physiological parameter based on the physiological measurement;
Comparing the physiological parameter with a predetermined threshold value, and
Based on the comparison, an indication is provided to the operator as to whether the patient has a physiological characteristic indicative of a therapeutic response to the renal neuromodulation therapy at the target site.
2. The neuromodulation/evaluation system of example 1, wherein the sensing element comprises a pressure sensing element, a flow sensing element, an impedance sensing element, and/or a temperature sensing element.
3. The neuromodulation/evaluation system of example 1 or 2, wherein the sensing element is configured for detecting a physiological measurement indicative of renal artery pulse velocity, and wherein the controller is configured for determining the renal artery wave velocity based on the physiological measurement.
4. The neuromodulation/evaluation system of any of examples 1-3, wherein:
the sensing element is configured to detect physiological measurements at a first branch of the renal artery and at a second branch of the renal artery, and
The controller is configured to:
determining a first physiological parameter based on physiological measurements taken from the first branch,
Determining a second physiological parameter based on physiological measurements taken from the second branch, comparing the first physiological parameter to the second physiological parameter, and
Based on the comparison, it is determined whether the first branch or the second branch is more receptive to renal neuromodulation therapy.
5. The neuromodulation/evaluation system of any of examples 1-3, wherein:
The sensing element is configured to detect physiological measurements at a branch vessel of the renal artery and at the renal artery, and
The controller is configured to:
Determining a first physiological parameter based on physiological measurements taken from the branch vessel,
Determining a second physiological parameter based on physiological measurements taken from the renal artery,
Comparing the first physiological parameter with the second physiological parameter, and
Based on the comparison, it is determined whether the branch vessel or the renal artery is more receptive to renal neuromodulation therapy.
6. A system, comprising:
A guidewire having a proximal portion, a distal portion configured to be positioned at a target site in a renal blood vessel of a human patient, and a sensing element positioned along the distal portion, wherein the sensing element is a pressure sensing element, a flow sensing element, an impedance sensing element, and/or a temperature sensing element;
A controller configured to be communicatively coupled to the sensing element, wherein the controller is further configured to:
obtaining one or more measurements related to a physiological parameter of a patient via a sensing element;
determining a physiological parameter based on the measurement;
Comparing the physiological parameter with a predetermined threshold value, and
Based on the comparison, an indication is provided to the operator as to the likelihood that the patient will have a therapeutic response to renal neuromodulation therapy at the target site.
7. The system of example 6, wherein the sensing element is one of a plurality of sensing elements positioned along a distal portion of the guidewire.
8. The system of example 6 or example 7, wherein the physiological parameter is renal wave velocity, and wherein the sensing element is configured to obtain a measurement for determining renal wave velocity.
9. The system of example 6 or example 7, wherein the physiological parameter is renal resistance, and wherein the sensing element is configured to obtain a measurement for determining renal resistance.
10. The system of example 6 or example 7, wherein the physiological parameter is average blood pressure, and wherein the sensing element is configured to obtain a measurement for determining average blood pressure.
11. The system of example 6 or example 7, wherein the physiological parameter is average blood flow velocity, and wherein the sensing element is configured to obtain a measurement for determining the average blood flow velocity.
12. The system of any of examples 6-11, wherein the sensing element is configured to obtain measurements from a main vessel of the renal artery, a main bifurcation of the renal artery, and/or one or more renal branches distal to the main bifurcation of the renal artery.
13. The system of any of examples 6-12, wherein the controller is further configured to indicate which portions of the blood vessel are more sensitive to neuromodulation therapy based on the physiological parameter.
14. The system of any of examples 6-13, wherein the controller is further configured to indicate which portions of the blood vessel are less sensitive to neuromodulation therapy based on the physiological parameter.
15. The system of any of examples 6-14, further comprising a neuromodulation catheter, and wherein the neuromodulation catheter comprises:
an elongate shaft defining a lumen therethrough, the elongate shaft having a proximal portion and a distal portion, wherein the distal portion is configured to be positioned at a target site, and
A plurality of electrodes spaced along a distal portion of the elongate shaft.
16. The system of example 15, wherein:
The guidewire is configured to be slidably positioned within a lumen of the elongate shaft, and
The controller is configured to be communicatively coupled to the plurality of electrodes, wherein the controller is further configured to:
Applying a first stimulus at and/or near a target site within a blood vessel;
detecting, via at least one electrode of the plurality of electrodes, a vascular impedance resulting from the first stimulus to determine a baseline impedance;
delivering neuromodulation energy to a target site within a blood vessel of a human patient via a distal portion of the elongate shaft;
applying a second stimulus at and/or near the target site within the vessel after delivering the neuromodulation energy;
Detecting a vascular impedance resulting from the second stimulus via at least one of the plurality of electrodes to determine a neuromodulated impedance, and
The efficacy of neuromodulation is assessed based at least in part on a comparison of the baseline impedance and the post-neuromodulation impedance.
17. The system of example 15, wherein the lumen is a first lumen, and wherein the neuromodulation catheter further comprises a second lumen extending along the elongate shaft and configured for delivering a medicament at and/or near a target site to provide the first and second stimuli.
18. The system of example 15, wherein the distal portion of the elongate shaft is configured to convert to a helical shape such that at least one electrode of the plurality of electrodes is configured to contact an inner wall of a blood vessel, and wherein at least one electrode of the plurality of electrodes is configured to deliver neuromodulation energy.
19. A method for assessing a patient for neuromodulation therapy, the method comprising:
Delivering a distal portion of a guidewire to a target site within a renal blood vessel of a human patient, wherein the distal portion of the guidewire includes a sensing element;
Obtaining a baseline measurement related to a physiological parameter of the patient via the sensing element;
determining a physiological parameter based on the baseline measurement;
Comparing the physiological parameter with a predetermined threshold value, and
Based on the comparison, an indication is made as to whether the patient will have a therapeutic response to renal neuromodulation therapy.
20. The method of example 19, wherein determining the physiological parameter includes determining a renal wave velocity and/or renal resistance.
21. The method of example 19, wherein determining the physiological parameter includes determining an average blood pressure and/or an average blood flow velocity.
22. The method of any one of examples 19-21, wherein:
obtaining baseline measurements includes:
physiological measurements are obtained from branch vessels of the renal blood vessels,
Obtaining physiological measurements from renal blood vessels;
determining the physiological parameter includes:
determining a first physiological parameter based on physiological measurements taken from the branch vessel, and
Determining a second physiological parameter based on physiological measurements obtained from the renal blood vessels;
Comparing the physiological parameters includes:
comparing the first physiological parameter with the second physiological parameter, and
The indication includes:
whether a branch vessel or a renal vessel is more readily accepted by renal neuromodulation therapy is determined.
23. The method of any one of examples 19-21, wherein:
obtaining baseline measurements includes:
Physiological measurements are obtained from a first branch vessel of the renal blood vessel,
Obtaining physiological measurements from a second branch vessel of the renal blood vessel;
determining the physiological parameter includes:
Determining a first physiological parameter based on physiological measurements taken from the first branch vessel, and
Determining a second physiological parameter based on physiological measurements obtained from the second branch vessel;
Comparing the physiological parameters includes:
comparing the first physiological parameter with the second physiological parameter, and
The indication includes:
determining whether the first branch vessel or the second branch vessel is more receptive to renal neuromodulation therapy.
24. The method of example 19, wherein:
obtaining baseline measurements includes measuring pressure and velocity within renal vessels, and
Determining the physiological parameter includes determining a renal wave velocity using the following formula:
where P is pressure, U is velocity, and ρ is the density of the blood.
25. The method of any of examples 19-24, further comprising:
advancing a neuromodulation catheter over the guidewire to a target site, and
Renal neuromodulation therapy is applied using the neuromodulation catheter.
Conclusion of V
The present disclosure is not intended to be exhaustive or to limit the technology to the precise form disclosed herein. Although specific embodiments are disclosed herein for illustrative purposes, various equivalent modifications can be made without departing from the technology, as will be recognized by those skilled in the relevant art. In some instances, well-known structures and functions have not been shown and/or described in detail to avoid unnecessarily obscuring descriptions of the embodiments of the technology. Although the steps of a method may be presented herein in a particular order, in alternative embodiments, the steps may have another suitable order. Similarly, certain aspects of the present technology disclosed in the context of particular embodiments may be combined or eliminated in other embodiments. Moreover, while advantages associated with certain embodiments may be disclosed in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit the various advantages disclosed herein to fall within the scope of the technology. Accordingly, the present disclosure and related techniques may encompass other embodiments that are not explicitly shown and/or described herein.
In this disclosure, the singular terms "a," "an," and "the" always include plural referents unless the context clearly dictates otherwise. Similarly, unless the word "or" is expressly limited to mean only a single item in a list of two or more items, except for other items, use of "or" in such a list is to be interpreted as including any single item in the list, (b) all items in the list, or (c) any combination of items in the list. In addition, the use of the term "comprising" or similar terms throughout this disclosure is used to denote the inclusion of at least the feature(s), such that any greater number of the same feature(s) and/or additional type(s) of features is not precluded. Directional terms such as "upper", "lower", "front", "rear", "vertical" and "horizontal" may be used herein to express and clarify the relationship between various elements. It should be understood that such terms do not denote absolute orientation. Reference herein to "one embodiment," "an embodiment," or similar language means that a particular feature, structure, operation, or characteristic described in connection with the embodiment may be included in at least one embodiment of the present technology. Thus, the appearances of such phrases or formulations herein are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, operations, or characteristics may be combined in any suitable manner in one or more embodiments.